Zika virus infects human Sertoli cells and modulates the integrity of the in vitro blood-testis barrier model.

Siemann DN, Strange DP, Maharaj PN, Shi PY, Verma S.

Citation

Siemann DN, Strange DP, Maharaj PN, Shi PY, Verma S. (2017) Zika virus infects human Sertoli cells and modulates the integrity of the in vitro blood-testis barrier model. Journal of Virology Sep 6. pii: JVI.00623-17

Abstract

Confirmed reports of ZIKV in human seminal fluid for months after the clearance of viremia suggest the ability of ZIKV to establish persistent infection in the seminiferous tubules, an immune privileged site in the testis protected by the blood-testis barrier, also called the Sertoli cell barrier (SCB). However, cellular targets of ZIKV in human testis and mechanisms by which the virus enters seminiferous tubules remain unclear. We demonstrate that primary human SCs were highly susceptible to ZIKV as compared to the closely related dengue virus and induced expression of IFN-alpha, key cytokines and cell-adhesion molecules (VCAM-1 and ICAM-1). Further, using an in vitro SCB model, we show ZIKV was released on the adluminal side of the SCB model with higher efficiency than the blood-brain barrier. ZIKV-infected SCs exhibited enhanced adhesion of leukocytes that correlated with decrease in the SCB integrity. ZIKV infection did not affect the expression of tight and adherens junction proteins such as ZO-1, claudin and JAM-A, however exposure of SCs with inflammatory mediators derived from ZIKV-infected macrophages led to the degradation of ZO-1 protein that correlated with increased SCB permeability. Taken together, our data suggest that infection of SCs may be one of the crucial steps by which ZIKV gains access to the site of spermatozoa development and identify SCs as a therapeutic target to clear testicular infections. The SCB model opens up opportunities to assess interactions of SCs with other testicular cells and test the ability of anti-ZIKV drugs to cross the barrier.IMPORTANCE Recent outbreaks of ZIKV, a neglected mosquito-borne flavivirus, have identified sexual transmission as a new route of disease spread, not reported for other flaviviruses. To be able to sexually transmit for months after clearance of the viremia, ZIKV must establish infection in the seminiferous tubules, a site for spermatozoa development. However, little is known about the cell types that support ZIKV infection in the human testis. Currently there are no models to study mechanisms of virus persistence in the seminiferous tubules. We provide evidence that ZIKV infection of human Sertoli cells, important component of the seminiferous tubules, is robust and induce strong antiviral response. The use in vitro Sertoli cell barrier to describe how ZIKV or inflammatory mediators derived from ZIKV-infected macrophages compromise the barrier integrity will enable studies to explore interaction of other testicular cells with Sertoli cells and test novel antivirals for clearing testicular ZIKV infection.